This research represents a long-term effort by the PI and colleagues to define the molecular, cellular and physiological mechanisms that underlie behavioral plasticity, using songbirds as a model. Experiments in many systems have now shown that a period of active gene expression (RNA and protein synthesis) is necessary for efficient consolidation of short-term memories into stable, long-lasting forms. More recently, the Immediate Early Genes (IEGs) have been implicated as primary molecular gents in this phenomenon. The PI has focused on one IEG as an exemplar (ZENK) and has shown that it is induced in specific regions of the zebra finch brain by normal day-to-day experiences, including both hearing song and active single. ZENK does not appear to be induced constitutively by just any physiological activity, however. For example, after a bird has listened to one song repeatedly, that particular song stops inducing a ZENK response though other songs still will. Songs also fail to induce ZENK when presented to juveniles who have not yet begun the process of song learning, or to older birds who were reared under conditions of severe social isolation. In the past project, this to older birds who were reared under conditions of severe social isolation. In the past project period, this research tested the hypothesis that such changes in Zenk responsiveness could be explained simply by quantity of electrophysiological activity (mean spike rate) elicited in each case. The results did not support this hypothesis. The specific aims proposed for the next research period will test a range of new hypothesis about the mechanisms by which recent experience, developmental age, and early rearing conditions an modulate IEG responses. The mechanisms under consideration span from the intracellular to the behavioral level: Aim 1- tests of environmental, sensory and temporal factors that may influence the specificity of the Zenk response. Aim 2- tests of electrophysiological correlates of ZENK induction, using multi-electrode recording techniques. Aim 3- tests of intracellular correlates of ZENK induction, focusing in particular on the CREB protein and other proteins that interact with the ZENK gene promoter. Aim 4- tests of ZENK regulation and function in the context of the circuit that controls song production. Collectively, these experiments will illuminate the possible role of the IEG response as a central integrative mechanism in the functioning nervous system. This program of basic research has fundamental applicability to issues of human health and disease, including various psychiatric conditions and learning disorders.